The controlled release of bioactive substances such as drugs has become an important mode of treatment for many diseases and disorders. Pharmaceutical manufacturers have introduced many products which are designed to gradually release bioactive substances at a therapeutically-useful rate and to spatially target the release. For example, the release rate may be controlled mechanically by a valving system, or physically, as by slow drug diffusion through protective encapsulation.
Iontophoresis is an electrochemical process which has found limited utility for the controlled application of charged agents such as metal ions, analgesics and anesthetics to afflicted bodily areas such as inflamed joints. Iontophoresis utilizes direct electrical current to drive ionized chemicals through the intact skin. For example, in aqueous media, sodium salicylate disassociates into ions. The salicylate ions responsible for the analgesic action of the salt are negatively charged. Accordingly, these active species can be driven through the skin by the repelling action of a cathodic current which is applied to a reservoir containing the active species. Thus, when ion-tophoresing salicylate through the skin, the electrode contacting the salicylate solution must be connected to the positive pole of a battery while the counter-electrode which contacts the skin at some remote point is connected to the negative pole to provide a return path for the current. Simple circuits effective to conduct ion-tophoresis are disclosed in U.S. Pat. No. 3,991,755, the disclosure of which is incorporated by reference herein.
However, special difficulties are encountered in therapeutic or experimental situations where it is desired to release discrete units of highly active agents in vivo. For example, in neuroscience, it is important to be able to deliver neurotransmitters or drugs to specific locations at specific times. In this way, the effect of these compounds on single neurons can be studied. Iontophoresis has been employed for drug delivery at the single neuron level, whereby a solution of an active electrolyte is placed in a micropipet and then "phoresed" out with a small current. Although widely used, this technique suffers from a number of disadvantages, primarily related to quantification control. It is also necessary to apply the active substance in combination with a relatively large quantity of a carrier liquid to the area to be treated or tested.
One electrochemical alternative to iontophoresis is presented by L. L. Miller et al. in Neuroscience Letters, 35, 101 (1983) and J. Amer. Chem. Soc., 105, 5271, 5278 (1983), who disclose electrodes which are used to deliver the neutral neurotransmitters dopamine (3, 4-dihydroxy-phenethylamine), glutamic acid and gamma-aminobutyric acid from their surfaces in response to an electrical signal. A compound electrode was constructed by coating an inert electrode with a polystyrene-based polymer film having the neutrotransmitter covalently bound to the polymer backbone through an amide linkage. At sufficiently negative potentials, cathodic reduction cleaved the amide bond and released the neurotransmitter into a small volume of aqueous buffer. The released amine was detected at a second electrode by its electrochemical oxidation or alternatively, analyzed by HPLC. Although this method permitted the release of a bioactive agent into a physiological medium, the amounts released at neutral pH were vey low, and could not be appreciably increased by increasing the amount of loaded polymer on the electrode, due to slow charge propagation within the film.
The use of such polymers for drug delivery is disadvantageous, since a separate chemical synthesis is required to incorporate the active species into the polymer. Furthermore, polymers bearing covalently-bound drugs cannot be easily reloaded once the drug has been released from the polymeric matrix. Therefore, a need exists for a electrochemical method for the controlled delivery of charged bioactive chemical species from an electrode into physiological media such as blood, lymph, spinal fluid and the like.